Efficacy and optimization of palivizumab injection regimens against respiratory syncytial virus infection

Abstract

Importance: Infection with the respiratory syncytial virus (RSV) is the leading cause of hospitalizations in children, accounting for more than 90,000 hospitalizations every year in the United States. For children who are at risk for severe RSV infections, the American Academy of Pediatrics recommends immunoprophylaxis with a series of up to 5 injections of the antibody palivizumab administered monthly, beginning on November 1 of each year. However, many practitioners initiate injections at the onset of RSV season as indicated by local surveillance.

Objectives: To evaluate the effectiveness of current regimens for palivizumab injections across different cities and to design an optimized regimen.

Design, setting, and participants: We performed a mathematical modeling study of the risk for hospitalization due to RSV infection. The model accounted for the pharmacokinetics of the antibody, the timing of the injections, and seasonal patterns of RSV, including geographic and year-to-year variability. We used the model to estimate the efficacy of current regimens, including the American Academy of Pediatrics recommendation, and to design a more effective injection regimen, the optimized fixed start (OFS), which uses city-specific initiation dates. Participants were the approximately 700,000 individuals who had specimens tested for RSV by National Respiratory and Enteric Virus Surveillance System laboratories in 18 US cities from July 1, 1994, through June 30, 2011 (a total of 725,741 tests).

Interventions: Different palivizumab injection regimens.

Main outcomes and measures: The primary outcome measure was reduction in hospitalizations due to RSV infections. The secondary measures were cost (number of palivizumab doses) and duration of protection (in days).

Results: The American Academy of Pediatrics-recommended 5-injection regimen is expected to reduce hospitalization risk by a median of 2.7% (range, -2.2% to 6.1%) compared with the conventional regimen based on RSV surveillance. The 5-injection OFS regimen is expected to further reduce risk by a median of 6.8% (range, 4.9% to 14.8%), and the 4-injection OFS regimen is expected to achieve efficacy comparable to that of the conventional 5-injection regimen while reducing costs by 20%.

Conclusions and relevance: Modified palivizumab regimens can improve protection for children at risk for severe outcomes of RSV infection and thereby lower rates of hospitalization due to RSV.

Figure 1. Estimated Serum Palivizumab Concentrations and Risk for Respiratory Syncytial Virus (RSV)

–Related Hospitalization for 2 Seasons in Atlanta, Georgia The graphs depict the efficacy of the seasonal and optimized fixed start (OFS) regimens (described in the Methods section). The weekly hospitalization risk was rescaled based on the peak of the season. Palivizumab concentrations of greater than 30 to 40 μg/mL are protective (gray bar) and reduce the hospitalization risk (reduction not shown). The OFS regimen has a longer duration of protection, which reduces hospitalization during extended seasons (A) and is not triggered prematurely (B).

Figure 2. Recommended Dates for Initial Injections in the Optimized Fixed Start (OFS) Palivizumab Strategy in 17 US Cities

The OFS strategy is detailed in Table 2. Varied shades in data points correspond to the shading in the date line.

Figure 3. Projected Relative Risk Reduction of 4 Palivizumab Regimens in 18 US Cities

The x-axis shows the improvement (reduction) in hospitalization risk relative to that achieved under the conventional seasonal regimen. Under the optimized fixed start (OFS) regimen, the median improvement compared with the seasonal regimen across cities is 6.8% (range, 4.9% to 14.8%). The regimens that initiate injections 30 days before the median start date across the 5 most recent seasons (MED30) and that recommend the first injection occur on November 1 (NOV1) also reduce risk beyond the seasonal regimen in many cities, but the reduction is less than that of the OFS regimen. The MED30 regimen is expected to under perform by at least 3% relative to the seasonal regimen in 4 cities (bars truncated; see Table 2 for details). The 4-injection OFS regimen (OFS4) is 20% less expensive than the seasonal regimen and is typically more protective, with a relative risk reduction of 1.9% (range, −4.2% to 9.5%).